EDNRA: A Key Target for Disease-Associated Angioplasty, Tumor Invasion, and Metabolic Regulation

1. About EDNRA

Endothelin A receptor (Endothelin Receptor Type A, EDNRA), a member of the G protein-coupled receptor (GPCR) family, is mainly expressed in endothelial and smooth muscle cells and is one of the primary receptors for endothelin-1 (ET-1). ET-1 binding to EDNRA mediates various physiological processes such as vascular contraction, cell proliferation, and inflammatory responses ^[1]. EDNRA plays a critical role in the development and homeostasis of the cardiovascular system, and its abnormal expression is closely associated with the development of several diseases, including hypertension, atherosclerosis, and intracranial aneurysms (IA) ^[2].

2. EDNRA Mechanism of Action

2.1 Ligand Binding and Receptor Activation

EDNRA has a high affinity for ET-1 and ET-2 but a weaker affinity for ET-3 ^[3]. Upon activation, it couples with Gq protein to activate the phospholipase C (PLC)-IP3 pathway, increasing intracellular calcium concentrations and thereby regulating vascular smooth muscle contraction and cell proliferation ^[4]. Additionally, EDNRA can activate the mitogen-activated protein kinase (MAPK) pathway via a β-arrestin-dependent mechanism, contributing to cell migration and inflammatory responses ^[5].

2.2 Gene Polymorphism and Structural Variations

Single nucleotide polymorphism (SNP): The rs1878406 C>T polymorphism in the EDNRA gene is linked to an increased risk of large artery atherosclerotic stroke, with the TT genotype reducing receptor function and causing vascular smooth muscle cell proliferation dysfunction ^[6]. The rs5333 T allele is identified as a protective factor for cerebral hemorrhage, whereas the rs5351 A allele is positively correlated with disease risk ^[7].
Copy number variation (CNV): In goats, the 1 Mb genomic region containing the EDNRA gene is duplicated, which is associated with coat color phenotypes. The increased copy number leads to overexpression of the receptor, potentially competitively binding to ET-3 and interfering with EDNRB signaling, thereby affecting melanocyte development ^[8].

2.3 Non-Coding RNA Regulation

MicroRNAs (miRNAs) regulate EDNRA expression by targeting EDNRA mRNA. For example, miR-342-3p inhibits EDNRA translation by binding to its 3'UTR, thereby alleviating vascular inflammation and thrombosis in deep vein thrombosis (DVT) ^[9]. MiR-1929-3p downregulates EDNRA to suppress NLRP3 inflammasome activation, mitigating hypertension-associated vascular remodeling ^[10].

3. EDNRA-Related Signaling Pathways

3.1 Canonical Gq/PLC/Calcium Signaling Pathway

Upon EDNRA activation, Gq protein triggers PLC to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces the release of Ca²⁺ from the endoplasmic reticulum, leading to vascular smooth muscle contraction and cell proliferation. This pathway is significantly activated in hypertension and atherosclerosis ^[11].

3.2 β-arrestin/MAPK Pathway

EDNRA binding to β-arrestin activates extracellular signal-regulated kinase (ERK) and p38 MAPK, promoting the phenotypic transition of vascular smooth muscle cells (e.g., from contractile to synthetic types) and participating in vascular remodeling. In colorectal cancer, this pathway promotes tumor progression through STAT3 phosphorylation activation ^[5].

3.3 Interactions with Other Receptors

EDNRA and EDNRB have antagonistic roles in vascular homeostasis: EDNRA mediates contraction and proliferation, while EDNRB induces relaxation by releasing nitric oxide (NO). In a pulmonary hypertension model, EDNRA inhibition enhances the protective effects of EDNRB ^[12].

4. Related Diseases

4.1 Cardiovascular Diseases

Hypertension and vascular remodeling: EDNRA overexpression exacerbates hypertension-induced vascular smooth muscle cell proliferation and vascular wall thickening by activating the NLRP3 inflammasome. In mouse models, EDNRA gene knockout alleviates pressure overload-induced cardiac remodeling ^[13].
Intracranial aneurysms (IA): The rs1878406 polymorphism in the EDNRA gene is positively associated with IA risk. Individuals with the T allele exhibit reduced vascular wall elasticity and increased susceptibility to hemodynamic damage. EDNRA knockout inhibits IA formation in mice ^[14].

4.2 Metabolic Diseases and Inflammation

In deep vein thrombosis (DVT), EDNRA upregulates inflammatory factors (e.g., TNF-α, IL-6) to promote vascular endothelial damage. MiR-342-3p alleviates thrombosis by inhibiting EDNRA ^[12]. EDNRA expression is elevated in obesity and diabetes-related vascular complications, contributing to vascular endothelial dysfunction.

4.3 Tumors and Other Diseases

In colorectal cancer, the EDN1/EDNRA/β-arrestin axis promotes tumor cell proliferation and invasion by regulating STAT3 phosphorylation ^[5]. In skin pigmentation disorders, EDNRA copy number variation competitively binds to ET-3, disrupting EDNRB-mediated melanocyte development and causing coat color whitening ^[8].

5. Drug Research Progress

Currently, drug development targeting EDNRA mainly focuses on nephrology and cardiology, with several small-molecule drugs already approved. Phase 2/3 pipeline drugs (e.g., SC-0062, sparsentan) show significant potential for reducing proteinuria and may address unmet clinical needs. Selective EDNRA/ETA antagonists and combination therapies are key directions for reducing side effects. Additionally, some antibody pipelines are under development for tumors, pulmonary hypertension, and pulmonary fibrosis. Below is a table of selected ongoing pipelines:

Drug	Drug Type	Indications	Developer	Development Stage
Gegregumab	Monoclonal Antibody	Pulmonary Arterial Hypertension	Hangzhou Honray Biopharmaceutical Co., Ltd.	Phase 2
Patecibart	Monoclonal Antibody	Tumor	-	Unclear
GMA-306	Bispecific Antibody	Pulmonary Arterial Hypertension	Hangzhou Honray Biopharmaceutical Co., Ltd.	Pulmonary Fibrosis
HH-103	Monoclonal Antibody	Solid Tumor	Hedgehog Co., Ltd.	Preclinical
WO2022262733	Bispecific Antibody	Tumor	Hangzhou Honray Biopharmaceutical Co., Ltd.	Drug Discovery

6. EDNRA-Related Products Recommendation

CUSABIO offers high-quality EDNRA-related recombinant proteins and antibodies to assist researchers in studying EDNRA mechanisms and clinical translation:

● EDNRA Recombinant Proteins

Recombinant Human Endothelin-1 receptor (EDNRA)-VLPs (Active); P007403HU

● EDNRA Antibodies

EDNRA (Getagozumab) Recombinant Monoclonal Antibody

CSB-RA007403MA3HU

Applications: ELISA

EDNRA Antibody

CSB-PA299262

Applications: ELISA,WB,IHC

References

[1] Davenport AP, et al. Endothelin. Pharmacol Rev. 2016;68(3):357-418.

[2] Zeng Y, et al. Associations of EDNRA and EDNRB polymorphisms with intracerebral hemorrhage. World Neurosurg. 2019;130:e804-e814.

[3] Braasch I, et al. The endothelin system: evolution of vertebrate-specific ligand-receptor interactions by three rounds of genome duplication. Mol Biol Evol. 2009;26(4):783-799.

[4] Yanagisawa M, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332(6163):411-415.

[5] Li X, et al. The EDN1/EDNRA/β-arrestin axis promotes colorectal cancer progression by regulating STAT3 phosphorylation. Oncogene. 2023; doi:10.1038/s41388-023-02620-5.

[6] Wei W, et al. EDNRA Gene rs1878406 Polymorphism is Associated With Susceptibility to Large Artery Atherosclerotic Stroke. Front Genet. 2022;12:783074.

[7] Zhang L, Sui R. Effect of SNP polymorphisms of EDN1, EDNRA, and EDNRB gene on ischemic stroke. Cell Biochem Biophys. 2014;70(2):233-239.

[8] Menzi F, et al. Genomic amplification of the caprine EDNRA locus might lead to a dose dependent loss of pigmentation. Sci Rep. 2016;6:28438.

[9] Pan Z, et al. MicroRNA-342-3p Loaded by Human Umbilical Cord Mesenchymal Stem Cells-derived Exosomes Attenuates Deep Vein Thrombosis by Downregulating EDNRA. Preprints. 2021; doi:10.21203/rs.3.rs-764341/v1.

[10] Zhou W, et al. MicroRNA-1929-3p participates in murine cytomegalovirus-induced hypertensive vascular remodeling through Ednra/NLRP3 inflammasome activation. Int J Mol Med. 2021;47(2):719-731.

[11] Lampmann T, et al. Experimental Induction of Intracranial Aneurysms in Rats: A New Model Utilizing a Genetic Modification within the EDNRA Gene. Brain Sci. 2022;12(9):1239.

[12] Mercier O, et al. Endothelin A receptor blockade improves regression of flow-induced pulmonary vasculopathy in piglets. J Thorac Cardiovasc Surg. 2010;140(3):677-683.

[13] Zhou W, et al. MicroRNA-1929-3p participates in murine cytomegalovirus-induced hypertensive vascular remodeling through Ednra/NLRP3 inflammasome activation. Int J Mol Med. 2022;49(1):27.

[14] Zhang Y, et al. miR-1929-3p Overexpression Alleviates Murine Cytomegalovirus-Induced Hypertensive Myocardial Remodeling by Suppressing Ednra/NLRP3 Inflammasome Activation. 2022; doi:10.3390/ijms23158409.

[15] Yasuno K, et al. Common variant near the endothelin receptor type A (EDNRA) gene is associated with intracranial aneurysm risk. Proc Natl Acad Sci U S A. 2011;108(49):19707-19712.